NEUROPATHOLOGY & BIOMARKER CORE: Project Summary/Abstract Nearly all aging related neurodegenerative diseases are characterized by accumulations of protein aggregates in selectively vulnerable regions of the CNS that define the neuropathology of each disorder, including frontotemporal degeneration (FTD), the second most common cause of dementia in patients <65 years of age. FTD is clinically heterogeneous and different clinical subtypes do not precisely predict the underlying neuropathology. The two major CNS signatures of neuropathologically defined FTD, referred to as frontotemporal lobar degeneration (FTLD), are tau and TDP-43 inclusions, and these forms of FTLD are known as FTLD-Tau and FTLD-TDP, respectively, while FUS inclusions define FLTD-FUS. Although FTLD-Tau, FTLD-TDP and FTLD-FUS account for ~45%, ~50% and ~5% of FTLD cases, respectively, clinically atypical Alzheimer?s disease (AD) is the underlying neuropathology in ~25% of FTD patients. About 25% of FTD is familial due to MAPT mutations, while mutations in C9orf72, GRN, TARDBP and several other genes are pathogenic for FTLD-TDP. The focus of the Neuropathology and Biomarker Core as well as of this Program Project Grant (PPG) renewal is FTLD-Tau, especially corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and Pick?s disease (PiD). Thus, a thorough postmortem examination of FTD patients followed in Core B of this PPG is essential to define the FTLD subtypes underlying clinical FTD and link them to genetic, imaging and biomarker findings as well as to begin to define strains of pathological tau associated with different FTLD-Tau subtypes and improve the diagnosis and treatment of FTD. Further, the collection of biofluids is essential for identifying FTD biomarkers to improve the antemortem diagnosis of FTD. Accordingly, Core D conducts postmortem neuropathology studies on all FTD patients and controls followed in Clinical Core B who consent to autopsy in addition to banking CNS tissue samples, plasma and cerebrospinal fluid (CSF) from FTD patients and controls while collaborating with all PPG Cores/Projects. Hence, this Neuropathology and Biomarker Core supports the goals of this PPG in the renewal period.